Our research suggests that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) resulted in rapid, robust and relatively sustained antidepressant and antisuicidal effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. The current protocol consists of studies designed to address 3 major questions: Study 1: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2: (Biomarkers of rapid response in bipolar depression). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: 1) Rapid antidepressant effects in treatment-resistant bipolar depression. We replicated our previous findings with ketamine in bipolar depression. In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist. In addition, we found rapid antisuicidal effects within 1 hour. 2) Sleep marker are a predictor of response to ketamine Electroencephalographic (EEG) sleep slow wave activity (SWA; EEG power between 0.6 and 4Hz) has been proposed as a marker of central synaptic plasticity. Decreased generation of sleep slow waves - a core feature of sleep in depression - indicates underlying plasticity changes in the disease. We found that Delta sleep ratio (DSR) at baseline, a measure of SWA, was positively correlated with reductions in depressive scores with ketamine treatment. 3) Genetics as a predictor of response to ketamine (rapid antidepressant effect) An animal study found that normal brain derived neurotrophic factor (BDNF) function is required for the antidepressant effects of ketamine. We should that in patients with major depressive disorder that MDD patients with the Val/Val BDNF allele were more likely to exhibit increased antidepressant responses to ketamine than BDNF Met carriers. 4) Synaptic potentiation is critical for the rapid antidepressant response to ketamine We used magnetoencephalographic recordings in 20 patients with treatment-resistant depression and found that patients with robust improvements in depressive symptoms 230 min after infusion of ketamine (responders) exhibited increased cortical excitability. Specifically, we found that stimulus-evoked somatosensory cortical responses increased after infusion with ketamine, relative to pretreatment responses in responders but not in treatment nonresponders. 5) Ketamines metabolites are important in its ressponse and side effects (patent filed) A diagnostic difference was observed in the metabolism and disposition of ketamine (bipolar depression versus major depressive disorder). Concentrations of (2S,5S;2R,5R)-HNK metabolites were related to nonresponse to ketamine in bipolar depression. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms (side effects of ketamine).